The present invention relates to compounds, compositions, apparatus and methods for treating a medical condition for which a photodynamic compound is indicated, particularly in the curative or prophylactic treatment of medical conditions such as atherosclerosis, cataracts, restenosis, secondary cataracts, endometrial ablation, bladder cancer, other cancers and proliferative diseases, inflammation and infection.
Photodynamic therapy is a method of treating a diseased tissue of a patient. Typically, the surgical procedure involves administering a photodynamic agent to a patient, such as via an intravenous injection, and then irradiating the target diseased tissue with a separate light source. The photodynamic agent following irradiation with light emits reactive oxygen species, such as singlet oxygen, which disrupt the surrounding cellular tissue.
A problem with prior art methods is that many of the photodynamic agents are relatively insoluble in physiologically acceptable media and they also tend to form aggregates in solution. Such adverse physicochemical properties necessitate complex formulations in order to provide useful materials for medical use. Moreover, as the formulations are typically administered by intravenous injection it is difficult to target the diseased tissue specifically.
Chemistry of Heterocyclic Compounds 23, 186-191 (1987) (Zhamkochyan el al.) disclose s various 5,10,15,20-tetra(4xe2x80x2-vinyl and -allyl phenyl)porphyrin derivatives and their Cu(II), Ni(II), CO(II) and Fe(III)Cl complexes.
Chemistry of Heterocyclic Compounds 23, 645-50 (1987) (Syrbu et al.) discloses monohaloalkyloxyphenyl-triphenyl-porphyrins and dimeric porphyrins.
Chemistry of Heterocyclic Compounds 25, 1149-53 (1989) (Syrbu et al.) discloses tetra-(carboxymethylenoxyphenyl)porphines and their ethyl esters.
Chem. Ber. 129(9), 1073-81 (1996) (Buchler et al.) discloses metalloporphyrin double deckers formed by reaction of 5-(4-hydroxyphenyl)-10,15,20-tris(4-methyl)phenylporphyrin with xcex1,xcfx89dibromoalkanes and 1,4-bis(3-bromopropyl)-2,5-dimethoxybenzene.
J.A.C.S. 112(6), 2440-2 (1990) (Manka et al.) discloses a tetraaminooxyphenylporphyrin derivative.
J. Chem. Soc., Perkin Trans. I no. 10, 2335-9 (1983) (Milgrom et al.) discloses 5,10,15,20-tetrakis(4-substituted phenoxy)porphyrin derivatives and their metal complexes for use as sensitisers for microheterogeneous water photooxidation.
J. Org. Chem. 59(24), 7473-8 (1994) (Schneider et al.) discloses 5,10,15,20-tetrakis(4-substituted phenoxy)porphyrin derivatives and their Cu and Zn complexes for potential use as antiviral/antitumour agents.
J. Org. Chem. 52(5), 827-36 (1987) (Lindsey et al) discloses the preparation of tetraphenylporphyrins.
Tet. Letts. 38(40), 7125 (1997) (Mehta et al.) discloses an anthraquinone porphyrin derivative for photodynamic therapy.
Tet Letts. 36(10), 1665-6 (1995) (Latouche et al.) discloses 5,10,15,20-tetrakis(4-(carboxymethylene)phenoxy)porphyrin derivatives and copper complexes in xe2x80x9cproteic mediumxe2x80x9d.
J. Chem. Soc., Perkin Trans. I no 22, 2667-9 (1993) (Mehta et al.) Discolors an acridone porphyrin derivative for photodynamic therapy.
Tet. Letts. 35(24), 4201-4 (1994) (Mehta et al.) discloses a porphyrin derivative linked to the anti-cancer drug chiorambucil for photodynamic therapy.
J. Heterocyclic Chem. 15(2), 203-8 (1978) (Little et al.) discloses covalently linked porphyrin dimers which may include a metal, such as V(IV) or Cu(II).
U.S. Pat. No. 5,594,136 relates to texaphyrins supported on a matrix. The matrix-supported texaphyrins may be used in the separation of neutral and anionic species, in applications concerning phosphate ester hydrolysis, magnetic resonance imaging and photodynamic therapy.
U.S. Pat. No. 5,284,647 relates to meso-tetraphenylporphyrin compounds which have a maximum of two substituents on the phenyl rings.
The present invention therefore seeks to provide improved compounds, compositions, apparatus and methods for treating a medical condition where photodynamic therapy is indicated and open the way for medical conditions which are not currently treated by photodynamic therapy.
According to a first aspect of the invention, there is provided a compound of formula I, 
wherein
R1, R2, R3, R4, R5, R6, R7, R8, and R9 independently represent H, lower alkyl, lower alkenyl and lower alkynyl, the latter three of which are optionally substituted or terminated by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR10, C(O)R11, C(O)OR12, C(O)NR13R14 and NR15R16; 
M represents a metallic element or a metalloid element;
X represents SH, Sxe2x80x94]2, OH, NHR15, CO2H, Cl, Br, I, NCO, NCS, CN, Cxe2x89xa1CH, CHxe2x95x90CH2, MgCl, ZnCl, Li, Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, SihaloR17R18, silyl, NO2, CHO C(O)]2O, C(O)halo, C(O)OR20, OC(O)halo, C(O)N3, thiocyano, or halobenzyl;
Each Y1, Y2 and Y3 is independently absent or represents O;
Z is absent or represents lower alkylene;
R10, R11, R12, R13, R14, and R16 independently represent H or lower alkyl;
R15 represents H, lower alkyl, aryl or lower alkylaryl;
R17, R18 and R19 independently represent H, lower alkyl, aryl or lower alkylaryl;
R20 represents H, lower alkyl, lower alkenyl or C(O)R21 where R21 represents an activating group for reaction to form an amide bond such as N-hydroxysuccinimide, N-hydroxybenzotriazole, or pentafluorophenyl ester; and
A-B and C-D independently represent CHxe2x95x90CH or C2xe2x80x94CH2;
which compounds or a pharmaceutically acceptable derivative thereof are referred to together hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
The term lower alkyl is intended to include linear or branched, cyclic or acyclic, C1-C20 alkyl which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkyl chain). Lower alkyl groups which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R22 and R23 may represent include C1-C18 alkyl, C1-C17 alkyl, C1-C16 alkyl, C1-C15 alkyl, C2-C15 alkyl, C3-C15 alkyl, C4-C15 alkyl, C5-C15 alkyl, C6-C15 alkyl, C7-C15 alkyl, C8-C15 alkyl, C8-C14 alkyl, C8-C12 alkyl and C8-C10 alkyl. Preferred lower alkyl groups which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R20 and R23 may represent include C6, C7, C8, C9, C10, C11, C12, C13, C14, C15 and C16 alkyl. Preferred lower alkyl groups which, R17, R18 and R19 may represent include C1-C3 alkyl, especially methyl or ethyl.
The terms lower alkenyl and lower alkynyl are intended to include linear or branched, cyclic or acyclic, C2-C20 alkenyl and C2-C20 alkynyl, respectively, each of which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkenyl or alkynyl chain). The term lower alkenyl also includes both the cis and trans geometric isomers. Lower alkenyl groups which R1, R2, R3, R4, R5, R6, R7, R8, R9, R20 and R23 may represent include C2-C18 alkenyl, C2-C17 alkenyl, C2-C16 alkenyl, C2-C15 alkenyl, C3-C15 alkenyl, C4-C15 alkenyl, C5-C15 alkenyl, C6-C15 alkenyl, C7-C15 alkenyl, C8-C15 alkenyl, C8-C13 alkenyl and C8-C12 alkenyl, C8-C10 alkenyl. Preferred lower alkenyl groups which R1, R2, R3, R4, R5, R6, R7, R8, R9, R20, and R23 may represent include C6, C7, C8, C9, C10, C11, C12, C13 and C14 alkenyl, especially C10 alkenyl.
Lower alkynyl groups which R1, R2, R3, R4, R5, R6, R7, R8, R9, R20 and R23 may represent include C2-C18 alkynyl, C2-C17 alkynyl, C2-C16 alkynyl, C2-C15 alkynyl, C2-C14 alkynyl, C3-C15 alkynyl, C4-C15 alkynyl, C5-C15 alkynyl, C6-C15 alkynyl, C7-C15 alkynyl, C8-C15 alkynyl, C8-C14 alkynyl, C8-C13 alkynyl, C8-C12 alkynyl and C8-C10 alkynyl. Preferred lower alkynyl groups which R1, R2, R3, R4, R5, R6, R7, R8, R9, R20 and R23 may represent include C6, C7, C8, C9, C10, C11, C12, C13 and C14 alkynyl, especially C10 alkynyl.
The term lower alkylene also includes linear or branched C1 to C20 alkylene which may be interrupted by oxygen (preferably no more than five oxygen atoms are present in each alkenyl chain). Preferred lower alkylene groups which Z, V and S may represent include C2-C20 alkylene, C4-C20 alkylene, C4-C18 alkylene, C4-C16 alkylene, C5-C16 alkylene, C6-C16 alkylene, C7-C16 alkylene, C8-C16 alkylene, C9-C16 alklylene, C10-C16 alkylene, C12-C16 alkylene and C14-C16 alkylene. Preferably, lower alkylene represents an alkylene having an even number of carbon atoms, for example C2, C4, C6, C8, C10, C12, C14, C16, C18 and C20 alkylene, especially C6, C10, C12, C14, C16 and C20 alkylene.
The term xe2x80x9carylxe2x80x9d includes six to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl, which groups are optionally substituted by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR10, C(O)R11, C(O)OR12, C(O)NR13R14 and NR15R16.
Halo groups which U and X may represent or include and with which R1, R2, R3, R4, R5, R6, R7, R8, R9 and M may optionally be substituted or terminated, include fluoro, chloro, bromo and iodo.
The term xe2x80x9cmetallic elementxe2x80x9d is intended to include a divalent or trivalent metallic element. Preferably, the metallic element is diamagnetic. More preferably, the metallic element is selected from Zn (II), Cu (II), La (III), Lu (III), Y (III), In (III) Cd (II), Mg (II), Al(III) and Ru. Most preferably, the metallic element is Zn (II) or Mg (II).
The term xe2x80x9cmetalloidxe2x80x9d is intended to include an element having physical and chemical properties, such as the ability to conduct electricity, that are intermediate to those of both metals and non-metals. The term metalloid element includes silicon (Si) and germanium (Ge) atoms which are optionally substituted with one or more ligands.
It will be appreciated that the terms metallic element and metalloid element include a metal element or a metalloid element having a positive oxidation state, all of which may be substituted by one or more ligands selected from halo, OH, OR23 wherein R23 is lower alkyl, lower alkenyl, lower alkynyl, aryl or alkylaryl as defined above.
For the avoidance of doubt, the term when X represents xe2x80x9cSxe2x80x94]2xe2x80x9d means the disulphide dimer, for example the disulphide dimer of the compound of formula I or the disulphide dimer of a photosensitizable compound as defined hereinafter. The compound of formula I or the photosensitizable compound is then bonded through the sulphur atom to an insoluble support thus forming a thio ether or a disulphide linkage.
The term when X represents xe2x80x9cC(O)]2Oxe2x80x9d means the anhydride, for example the anhydride of the compound of formula I, the anhydride of an insoluble support or an anhydride of a photosensitizable compound as defined hereinafter.
Preferred compounds of the invention include those in which each Y1, Y2 and Y3 represents oxygen, or each Y1, and Y3 represents oxygen and each Y2 is absent.
Further preferred compounds of the invention include those in which one or more of R1, R2, R3, R4, R5, R6, R7, R8 and R9 (preferably all) represent lower alkyl and each Y1, Y2 and Y3 represents oxygen, or each Y1 and Y3 represents oxygen and each Y2 is absent and one or more of R1, R3, R4, R6, R7 and R9 (preferably all) represent lower alkyl and R2, R5 and R8 (preferably all) represent H.
Further preferred compounds of the invention include those wherein X represents SH, Sxe2x80x94]2, OH, CHxe2x95x90CH2, Cxe2x89xa1CH, CO2H, NHR15, halo, C(O)halo, C(O)OR20, silyl, Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, SihaloR17R18, wherein R17 is lower alkyl, preferably methyl or ethyl.
Preferred compounds of the invention include those wherein:
R1, R2, R3, R4, R5, R6, R7, R8 and R9 independently represent H or lower alkyl;
M represents a metallic element, a silicon atom, or a germanium atom;
Each Y1, Y2 and Y3 represents oxygen, or each Y1 and Y3 represents oxygen and each Y2 is absent; and
Z is absent or represents lower alkylene.
More preferred compounds of the invention include those wherein:
R1, R2, R3, R4, R5, R6, R7, R8 and R9 independently represent linear or branched, cyclic or acyclic, C6-C16 alkyl and each Y1, Y2 and Y3 represents oxygen; or
R1, R3, R4, R6, R7 and R9 independently represent linear or branched, cyclic or acyclic, C6-C16 alkyl, R2, R5 and R8 represent H, each Y1 and Y3 represents oxygen and each Y2 is absent;
M represents Zn (II), La (III), Lu (III), Y (III), In (III), Cd (II), Mg (II), Al (III), Ru, a silicon atom or a germanium atom;
X represents SH, Sxe2x80x94]2, CHxe2x95x90CH2, Cxe2x89xa1CH, OH, CO2H, NHR15, halo, Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, SihaloR17R18, wherein R17 represents methyl or ethyl; and
Z represents lower alkylene having an even number of carbon atoms.
Particularly preferred compounds of the invention include those wherein
R1, R2, R3, R4, R5, R6, R7, R8 and R9 independently represent, n-C6H13, n-C8H17, n-C10H21, n-C12H25, n-C14H29, or n-C16H33 and each Y1, Y2 and Y3 represents oxygen; or
R1, R3, R4, R6, R7 and R9 independently represent n-C6H13, n-C8H17, n-C10OH21, n-C12H25, n-C14H29, or n-C16H33, R2, R5 and R8 represent H, each Y1 and Y3 represents oxygen and each Y2 is absent;
M represents Zn (II) or Mg (II);
X represents SH, Sxe2x80x94]2, CHxe2x95x90CH2, Cxe2x89xa1CH, OH, CO2H, NHR15, halo, Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, SihaloR17R18, wherein R17 represents methyl or ethyl; and
Z represents n-C6H12, n-C8H16, n-C10H20, n-C12H24, n-C14H28, n-C16H32, n-C18H36, or n-C20H40, each of which groups are optionally interrupted by oxygen.
Most preferred compounds of the invention include those wherein:
R1, R2, R1, R4, R5, R6, R7, R8 and R9 represent n-C6H13, n-CH10H21 or n-C16H33 and each Y1, Y2 and Y3 represents oxygen; or
R1, R3, R4, R6, R7 and R9 independently represent n-C6H13, n-C10H21 or n-C16H33, R2, R5 and R8 represent H, each Y1 and Y3 represents oxygen and each Y2 is absent;
M represents Zn (II) or Mg (II);
X represents SH, Sxe2x80x94]2, CHxe2x95x90CH2 or Si (halo)3; and
Z represents n-C6H12, n-C10H20, n-C12H24, n-C16H32, (CH2)12xe2x80x94(CH2)2 (CH2)6xe2x80x94Oxe2x80x94(CH2)2 or (CH2)16xe2x80x94Oxe2x80x94(CH2)2.
Most preferred compounds of the invention include the compounds of Examples 67 to 81 described hereinafter.
According to the invention there is also provided a process for the preparation of the compound of formula I, when A-B represents CH2xe2x80x94CH2 and C-D represents CHxe2x95x90CH or A-B represents CHxe2x95x90CH and C-D represents CH2xe2x80x94CH2, which comprises the reduction of a compound of formula I wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, M, X, Y1, Y2, Y3 and Z are as defined in formula I and A-B and C-D represent CHxe2x95x90CH.
The reduction may be accomplished using methods which are well known to those skilled in the art. For example, the reduction may be accomplished with a mixture of potassium hydroxide, an aryl sulphonylhydrazide, such as p-toluenesulphonylhydrazide, and pyridine at a temperature of between 80xc2x0 C. to 110xc2x0 C., preferably a temperature of 100xc2x0 C. to 105xc2x0 C. (R Bonnett et al., Biochem J. (1989) 261, p277-280).
An alternative synthetic route to the compounds of formula I, when A-B and C-D represent CHxe2x95x90CH, comprises the reaction of a compound of formula II: 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y1, Y2, Y3 and Z are as previously defined for formula I, A-B and C-D represent CHxe2x95x90CH, with a metallic element M or a metalloid element M as previously defined for a compound of formula I.
Typically, the reaction is performed using an appropriate metal salt, such as magnesium perchlorate or zinc acetate, in a suitable solvent (E Dietel et al, Journal of the Chemical Society, Perkin Transactions. II, 1998, p 1357 to 1364. For example, when the metallic element is Zn the reaction may be performed using an anhydrous zinc salt such as Zn(OAc)2 or ZnCl2 in anhydrous tetrahydrofuran at reflux temperature of the reaction.
A further alternative synthetic route to the compounds of formula I, when A-B and C-D both represent CH2xe2x80x94CH2, involves reducing a compound of formula II wherein R1, R2, R3, R4, R1, R6, R7, R8, R9, X, Y1, Y2, Y3 and Z are as defined above, A-B and C-D represent CHxe2x95x90CH, and reacting the resultant reduced form of compound II with a metallic element M or a metalloid element M as previously defined.
A still yet further alternative synthetic route to the compounds of formula I, when A-B represents CH2xe2x80x94CH2 and C-D represents CHxe2x95x90CH, or A-B represents CHxe2x95x90CH and C-D represents CH2xe2x80x94CH2, involves reducing a compound of formula II wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y1, Y2, Y3 and Z are as defined above, A-B and C-D represent CHxe2x95x90CH, and reacting the resultant reduced form of compound II with a metallic element M or a metalloid element M as previously defined.
A compound of formula II may be prepared by conversion of the Zxe2x80x94F functional group of a compound of formula III: 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y1, Y2, Y3, Z, A-B and C-D are as previously defined for formula II, and F represents OH or a lower alkylene-CHxe2x95x90CH2 group, into the desired ZX functional group, wherein X is as previously defined for formula II.
For example, when X is SH or Sxe2x80x94]2 in formula II, the reaction may be accomplished via formation of an isothiuronium salt, from a compound of formula III when F represents OH, using reagents and conditions which are well known to those skilled in the art (see I Chambrier et al., Synthesis, 1995, p1283 to 1286).
Typically, lie Zxe2x80x94OH alcohol functionality group of a compound of formula III is first derivatised into a Z-OSO2R22 group, wherein R22 is lower alkyl or phenyl, both of which may be optionally substituted by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR10, C(O)R11, C(O)OR12, C(O)NR13R14 and NR15R16, using methods which are well known to those skilled in the art. For example, the Zxe2x80x94OH alcohol functionality compound of formula III may be mesylated by reaction with MeSO2Cl in an appropriate solvent, such as dichloromethane, at a temperature of 10xc2x0 C. to 30xc2x0 C. The resultant mesylate group may then be displaced by reaction with thiourea to form an isothiouronium salt. Typically, the reaction is performed in THF/ethanol solvent mixture which has optionally been deoxygenated, under reflux in the dark, preferably under an inert atmosphere of nitrogen.
A compound of formula II when X represents SH may be prepared by the basic hydrolysis of the thiouronium salt in a THF/ethanol solvent mixture, for example using aqueous sodium hydroxide, under reflux and under an inert atmosphere, such as a nitrogen atmosphere.
A compound of formula II when X represents Sxe2x80x94]2 may be prepared by the basic hydrolysis of the thiouronium salt in a THF/ethanol solvent mixture, for example using aqueous sodium hydroxide, at reflux temperature of the reaction mixture under an oxygen atmosphere.
When X is CHxe2x95x90CH2 in formula II and Z represents a lower alkylene that is interrupted by oxygen, the reaction may be accomplished via conversion of the Zxe2x80x94OH alcohol functionality group of a compound of formula III into a Zxe2x80x94OSO2R22 group, wherein R22 is as previously defined. For example, the Zxe2x80x94OH alcohol functionality of the compound of formula III may be mesylated by reaction with MeSO2Cl. The resultant mesylate group may then be displaced by reaction with the appropriate alkenoate, for example sodium butenoate, in an appropriate organic solvent such as THF under reflux.
A compound of formula III may be prepared by reaction of four molar equivalents of pyrrole with one molar equivalent of a compound of formula V: 
wherein Z and F are as previously defined for a compound for formula III, and when F represents OH the alcohol functionality is optionally protected with a suitable protecting group, for example an acetyl group, using methods which are well known to those skilled in the art, and with one molar equivalent of each compounds of formulae VI, VII and VIII: 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y1, Y2, Y3 are as previously defined for a compound of formula III.
It will be appreciated that when compounds of formula VI, VII and VIII are identical, the reaction is conducted with 3 molar equivalents of one of the compounds of formula VI, VII or VIII.
Preferably, the reaction is carried out under acidic conditions by methods known to those skilled in the art (R G Little et al, Journal of Heterocyclic Chemistry, 1975, Vol 12, p343). Typically, a mixture of one molar equivalent of a compound of formula V, VI, VII and VIII and four molar equivalents of pyrrole in an appropriate solvent, such as an organic acid for example propionic acid, optionally with the addition of a mineral acid such as hydrochloric, hydrobromic, hydroiodic, or sulphuric acid, optionally with the addition of a Lewis acid such as zinc chloride or aluminium trichloride, heated under reflux for 1 to 4 hours, preferably four hours.
The compounds of formula V, VI, VII and VIII and derivatives thereof, when neither commercially available nor subsequently described, may be obtained using conventional synthetic procedures in accordance with standard text books on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.
For example, the compounds of formula V may be prepared from reaction of a compound of formula IX: 
with a compound of formula Fxe2x80x94Zxe2x80x94W, wherein Z and F are as previously defined for a compound of formula V, and W represents a leaving group, such as halo or W represents OH.
Typically, when W represents a leaving group such as halo the reaction is performed in a suitable organic solvent, such as methyl ethyl ketone or dichloromethane, under basic conditions, for example by using K2CO3, Na2CO3, pyridine or triethylamine, optionally at reflux temperature of the reaction mixture.
Typically, when W represents OH the reaction is performed in a suitable organic solvent such as dry tetrahydrofuran (THF) in the presence of triphenylphosphine and an azodicarboxylate, for example diisopropyl-azo dicarboxylate).
The compounds of formula VI, VII, and VIII may be prepared from reaction of a compound of formula X: 
wherein Y1, Y2 and Y3 are as previously defined before for a compound of formula III, or a suitably mono- or di-protected phenol derivative thereof, with a compound of formula R1W, R2W, R3W, R4W, R5W, R6W, R7W, R8W or R9W wherein R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as previously defined for a compound of formulae VI, VII and VIII, respectively, and W is a leaving group, such as halo.
Typically, the reaction is performed in a suitable organic solvent, such as methyl ethyl ketone or dichloromethane, under basic conditions, for example by using K2CO3, Na2CO3, pyridine or triethylamine, optionally at reflux temperature of the reaction mixture.
It will be appreciated by persons skilled in the art that, within certain of the processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps.
It will also be appreciated that various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formula I.
In a further aspect, the present invention provides a composition comprising an insoluble support and a compound of the invention of formula I. Preferably, the insoluble support is also biocompatible.
By the term xe2x80x9cinsolublexe2x80x9d we mean that the support does not dissolve or decompose in aqueous solution under normal physiological conditions over the intended timescale for photodynamic ability (ie reactive oxygen species production) of the photosensitizable compound. The timescale would be relatively short for an insertable/removable medical device for example 1 to 180 minutes, or many years for semi-permanent or permanent implanted medical devices. In other words, we mean that the support does not dissolve or decompose when implanted in or administered to a human or animal, during the desired period of treatment. By the term xe2x80x9cbiocompatiblexe2x80x9d we mean that the support is in a form that does not produce an adverse, allergic or other untoward reaction when administered to a human or animal in accordance with the invention.
The insoluble support enables the composition of the invention to be administered to a patient directly to the disease site without the need for administration by injection. This avoids the necessity for the photosensitizable compound to reach and accumulate at the target site, as is necessary with conventional photodynamic therapy, because the device is applied directly to the target site. Furthermore, the insoluble support eliminates or substantially reduces the dispersal and accumulation of the photosensitizable, compound in non-target tissues, thereby minimising chemical toxicity and damage to healthy non-target tissue following irradiation with light of the appropriate wavelength or indeed from activation by sunlight and other environmental light sources. Moreover, unless deliberately left in the body, when the support is subsequently withdrawn, no compound of the invention is left in the body.
Preferably, the solid support comprises polyethylene; polypropylene; polystyrene; polyacrylamide; polyamide; a resin for solid phase oligopeptide and/or oligonucleotide synthesis, such as a Merrifield resin; a natural or synthetic polysaccharide; a silicon derivative such as a functionalised silica, a glass, a silicone or a silicone rubber; an alumina; a noble metal, preferably a gold film optionally mounted on a glass surface; or a porous solid such as a controlled pore glass, a gel permeation material or a zeolite.
The insoluble support may be flexible, such as a flexible membrane, or a rigid support. Preferably, the insoluble support is coated and/or impregnated with the photosensitizable compound. More preferably, the photosensitizable compound is fixed to the surface of the insoluble support, optionally via a covalent bond, and optionally includes a bifunctional spacer molecule to space the compound from die insoluble support.
A compound fixed to the surface of the insoluble support may be represented by formula XI: 
wherein R1, R2, R3, R4, R5, R6, R7; R8 and R9, A-B, C-D, M, Z, Y1, Y2 and Y3 are as previously defined for a compound of formula I; V is absent or represents lower alkylene or an alkylaryl group; IS represents the insoluble support; (UX) represents a linkage derived from reaction between a group X of a compound of the invention of formula I and a group U of the insoluble support, wherein X is as defined for a compound of formula I, and U represents the group on the insoluble support for bonding with X, namely U represents OH, NHR15, SH, CO2H, Cl, Br, I, NCO, NCS, CN, Cxe2x89xa1CH, CHxe2x95x90CH2, MgCl, ZnCl, Li, Si(OR17)3, SIR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, SihaloR17R18, silyl, NO2, CHO, C(O)]2O, C(O)halo, C(O)OR20, OC(O)halo, C(O)N3, thiocyano or halobenzyl.
Preferably, the group X of the compound of the invention of formula I represents SH, Sxe2x80x94]2, CHxe2x95x90CH2, halo, C(O)]2O, C(O)OR20, Cxe2x89xa1CH, NHR15, Si (halo)3 or OH.
Preferably, when the group X of the compound of formula I represents CO2R20 then the group U of the insoluble support represents NHR15. Preferably, when the group X of the compound of formula I represents NHR15 then the group U of the insoluble support represents CO2R20. Preferably, when the group X of the compound of formula I represents CHxe2x95x90CH2 then the group U of the insoluble support represents CHxe2x95x90CH2 or Cxe2x89xa1CH, or alternatively the group U is absent and the photosensitizable compound is linked to the insoluble support by using a dopant such as acrylic acid. Preferably, when the group X of the compound of formula I represents OH then the group U of the insoluble support represents Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, or SihaloR17R18. Preferably, when the group X of the compound of formula I represents SH or Sxe2x80x94]2 then the insoluble support includes a noble metal. Preferably, when the group X of the compound of formula I represents Cxe2x89xa1CH then the group U of the insoluble support represents Cl, Br, I, Cxe2x89xa1CH, CHxe2x95x90CH2, MgCl or ZnCl, or the group U is absent and the compound of formula I is linked to the insoluble support by using a dopant such as acrylic acid.
It will be appreciated that a composition of formula XI may also be represented by a compound of formula XII. 
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Y1, Y2, Y3, Z, A-B, C-D and M are as previously defined for a compound of formula I, IS represents the insoluble support, V is absent or represents lower alkylene or an alkylaryl group; and E represents a linkage selected from an ether, thioether, ester, keto, poly(alkyloxy), amide, amine, carbamate, urea, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Si(OR17)2xe2x80x94, xe2x80x94SiR18R19xe2x80x94, xe2x80x94SiR17R18xe2x80x94, amino alcohol, amino acyl, alkylene, lower alkenyl, aryl or lower alkylaryl wherein R17, R18 and R19 are as defined hereinbefore.
Preferably, E represents alkylene, ether, amide, silyloxy, alkynyl, alkenyl, thioether, NR15, (CH2CH2O)m, keto, ester, or phenyl wherein m represents 1 to 10 and R15 is as previously defined hereinbefore.
According to a further aspect of the invention there is provided a process for the preparation of a composition of formula XII which comprises reacting a compound of the invention of formula I as previously defined with a compound of formula XIII: 
wherein IS, V and U are as defined above.
It will be appreciated that the X groups present on a compound of the invention react with available groups, termed U, present on or previously inserted into, the insoluble support. The combination of reactive groups U and X gives rise to the composition of the invention wherein the compound of the invention and the insoluble support are linked via a linkage such as ether, ester, amide, amine, carbamate, urea, xe2x80x94CHxe2x95x90CHxe2x80x94, keto, poly(alkyloxy), xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Si(OR17)2xe2x80x94, SiR18R19xe2x80x94, xe2x80x94SiR17R18xe2x80x94, amino alcohol, aminoacyl, alkylene, lower alkenyl, aryl or lower alkylaryl.
It will be appreciated that the reactive U group of the insoluble support may be either initially present or introduced by semi-synthesis (for example from materials derived from natural sources) or by ab initio chemical synthesis.
The choice of reaction conditions to link a compound of formula XII with a compound of formula XIII will depend on the nature of the X and U groups. Such conditions are well known to those skilled in the art. For example, if both U and X independently represent CHxe2x95x90CH2 or Cxe2x89xa1CH then the composition may be formed using for example, free radical-induced polymerisation, by halogenating U and/or X, and using metal-mediated cross coupling or standard alkyne coupling chemistry (Advanced Organic Chemistry, J March, Wiley Interscience, 4th Edition, p449-463; p714-715; p194; and p744). Alternatively, or additionally, if X represents CHxe2x95x90CH2 or Cxe2x89xa1CH and the insoluble support is a polymeric compound having no complementary U groups, then the photosensitizable compound may be linked to the polymeric support by using a dopant, such as an acrylic acid. The dopant may be incorporated into the polymeric support to provide a binding site for the photosensitizable compound or the dopant may be bonded to the photosensitizable compound and the resultant compound copolymerized with the polymeric support.
Reagents such as carbodiimides, 1,1xe2x80x2-carbonyldiiaidazole, cyanuric chloride, chlorotriazine, cyanogen bromide and glutaraldehyde, and processes such as use of mixed anhydrides, reductive amination and metal-assisted cross-couplings of halogenated compounds with organometallic compounds may also be used to couple the photosensitizable compound to the insoluble support.
According to a further aspect of the invention, there is provided a composition for the in vivo delivery of a photosensitizable compound to a target tissue comprising a photosensitizable compound and a biocompatible insoluble support, wherein the photosensitizable compound comprises a macrocycle having at least four unsaturated five-membered nitrogen containing rings.
The term xe2x80x9cunsaturated five-membered nitrogen containing ringxe2x80x9d includes pyrrole, dihydropyrrole, pyrroline and isomers thereof.
Preferably, the photosensitizable compound comprises a benzoporphyrin, a porphycene, a purpurin, an etiopurpurin, a chlorophyll, an haematoporphyrin, a phorbine, a chlorphyrin, a verdin, a bacteriochlorin, a porphyrinogen, a phthalocyanine, or a mixture of any two or more of these, or a pharmaceutically acceptable derivative thereof.
Preferably, the photosensitizable compound is a porphycene, a purpurin, a chlorophyll, a phthalocyanine, or a benzoporphyrin or a derivative of any of these compounds. For example, each of the four unsaturated five-membered nitrogen containing rings of the purpurin may be independently substituted with a lower alkyl, preferably an ethyl group. Each of the phenyl rings of the phthalocyanine may independently include a sulphate, amino, nitro, hydroxy, or carboxyl group.
The composition of the present invention comprising a photosensitizable compound and the insoluble support is preferably a compound of formula XIV: 
wherein PC represents a photosensitizable compound comprising a benzoporphyrin, a porphycene, a purpurin, an etiopurpurin, a chlorophyll, an haematoporphyrin, a phorbine, a chlorphyrin, a verdin, a bacteriochlorin, a porphyrinogen, a phthalocyanine, or a mixture thereof, IS represents the biocompatible insoluble support, (UX) represents a linkage derived from reaction between a group X of the photosensitizable compound and a group U of the insoluble support, wherein X represents NHR15, OH, SH, Sxe2x80x94]2, CO2H, Cl, Br, I, NCO, NCS, CN, Cxe2x89xa1CH, CHxe2x95x90CH2, MgCl, ZnCl, Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, SihaloR17R18, silyl, NO2, CHO, C(O)halo, C(O)OR20, C(O)]2O, OC(O)halo, C(O)N3, thiocyano, or halobenzyl, and U represents NHR15, OH, SH, CO2H, Cl, Br, I, NCO, NCS, CN, Cxe2x89xa1CH, CHxe2x95x90CH2, MgCl, ZnCl, Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, SihaloR17R18, silyl, NO2, CHO, C(O)halo, C(O)OR20, C(O)]2O, OC(O)halo, C(O)N3, thiocyano, or halobenzyl, wherein R15, R17, R18 and R19 are as previously defined for a compound of formula I, and R20 represents H, lower alkyl, lower alkenyl or C(O)R21 where R21 represents an activating group for reaction to form an amide bond such as N-hydroxysuccinimide, N-hydroxybenzotriazole, or pentafluorophenyl ester.
It will be appreciated that the group X may be present in the photosensitizable compound per se, for example, a chlorophyll includes a group X representing CHxe2x95x90CH2 and CO2R20 where R20 represents lower alkenyl, or the group X may be introduced into the photosensitizable compound by ab initio chemical synthesis.
Preferably, the photosensitizable compound is a benzoporphyrin and the group X represents CO2R20 or CHxe2x95x90CH2, a porphycene and the group X represents NHR15 or CO2R20, a purpurin and the group X represents CO2R20 or CHxe2x95x90CH2, a chlorophyll and the group X represents CO2R20 or CHxe2x95x90CH2, an haematoporphyrin and the group X represents CO2R20, CHxe2x95x90CH2 or OH, an etiopurpurin and the group X represents CO2R20, a phorbine and the group X represents CO2R20, CHxe2x95x90CH2, OH or SH, a verdin and the group X represents CO2R20, a chlorphyrin and the group X represents Cxe2x89xa1CH, a bacteriochlorin and the group X represents CO2R20, CHxe2x95x90CH2 or SH, or a porphyrinogen and the group X represents CO2R20 CHxe2x95x90CH2 or OH.
Preferably, when the group X of the photosensitizable compound represents CO2R20 then the group U of the insoluble support represents NHR15. Preferably, when the group X of the photosensitizable compound represents NHR15 then the group U of the insoluble support represents CO2R20. Preferably, when the group X of the photosensitizable compound represents CHxe2x95x90CH2 then the group U of the insoluble support represents CHxe2x95x90CH2 or Cxe2x89xa1CH, or alternatively the group U is absent and the photosensitizable compound is linked to the insoluble support by using a dopant such as acrylic acid. Preferably, when the group X of the photosensitizable compound represents OH then the group U of the insoluble support represents Si(OR17)3, SiR18(OR17)2, SiR18R19(OR17), Sihalo3, Sihalo2R17, or SihaloR17R18. Preferably, when the group X of the photosensitizable compound represents SH or Sxe2x80x94]2 then the insoluble support includes a noble metal. Preferably when the group X of the photosensitizable compound represents Cxe2x89xa1CH then the group U of the insoluble support represents Cl, Br, I, Cxe2x89xa1CH, CHxe2x95x90CH2, MgCl or ZnCl, or the group U is absent and the photosensitizable compound is linked to the insoluble support by using a dopant such as acrylic acid.
Preferably, the photosensitizable compound includes a spacer group S to which the X group is attached, wherein S represents lower alkylene or an alkylaryl group.
Preferably, the insoluble support includes a spacer group V to which the U group is attached, wherein V represents lower alkylene or an alkylaryl group.
Preferably the photosensitizable compound includes a metallic or a metalloid element bonded to a nitrogen atom, preferably to a pyrrole nitrogen atom, of the photosensitizable compound.
It will be appreciated that a composition of the present invention comprising a photosentizable compound and the insoluble support may also be represented by a compound of formula XV. 
wherein IS and PC are as previously defined for a compound of formula XIV, V and S are both absent or independently represent lower alkylene or an alkylaryl group, and E represents a linkage selected from an ether, thioether, ester, keto, poly(alkyloxy), amide, amine, carbamate, urea, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Si(OR17)2xe2x80x94, xe2x80x94SiR18R19xe2x80x94, xe2x80x94SiR17R18xe2x80x94, amino alcohol, amino acyl, alkylene, lower alkenyl, aryl or lower alkylaryl wherein R17, R18 and R19 are as defined hereinbefore.
Preferably, E represents alkylene, ether, amide, silyloxy, alkynyl, alkenyl, thioether, NR15, (CH2CH2O)m, keto, ester, or phenyl, wherein m represents 1 to 10 and R15 is as previously defined hereinbefore.
In yet a further aspect, the present invention provides a process for the preparation of the composition of the invention comprising a photosensitizable compound and the insoluble support, which is preferably a compound of formula XIV or XV, as defined hereinbefore.
Preferably, the insoluble support is coated and/or impregnated with the photosensitizable compound. More preferably, the photosensitizable compound is fixed to the surface of the insoluble support, optionally via a covalent bond and optionally includes a bifunctional spacer molecule to space the photosensitizable compound from the insoluble support.
Preferably, the process for the preparation of a composition of the present invention comprises reacting a compound of formula XVI: 
wherein PC-S-X together represents the photosensitizable compound, X is as previously defined for a compound of formula XIV, PC represents a benzoporphyrin, a porphycene, a purpurin, an etiopurpurin, a chlorophyll, an haematoporphyrin, a phorbine, a chlorphyrin, a verdin, a bacteriochlorin, a porphyrinogen, a phthalocyanine, or a mixture of any two or more of these, and S is absent or represents lower alkylene or an alkylaryl group, with a compound of formula XVII: 
wherein IS-V-U together represents the insoluble support, U is as previously defined for a compound of formula XIV and V is absent or represents lower alkylene or an alkylaryl group.
It will be appreciated that the X groups of the photosensitizable compound react with available groups, termed U, present on or previously inserted into, the insoluble support. The combination of reactive groups U and X gives rise to the composition of the invention wherein the photosensitizable compound and the insoluble support are linked via a linkage such as ether, ester, amide, amine, carbamate, urea, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, keto, poly(alkyloxy), xe2x80x94Si(OR17)2xe2x80x94, SiR18R19xe2x80x94, xe2x80x94SiR17R18xe2x80x94, amino alcohol, amino acyl, alkylene, lower alkenyl, aryl or lower alkylaryl.
It will be appreciated that the reactive X group of the photosensitizable compound and the reactive U group of the insoluble support may be either initially present or introduced by semi-synthesis (for example from materials derived from natural sources) or by ab initio chemical synthesis.
The choice of reaction conditions to link a compound of formula XVI with a compound of formula XVII will depend on the nature of the X and U groups. Such conditions are well known to those skilled in the art. For example, if both U and X independently represent CHxe2x95x90CH2 or Cxe2x89xa1CH then the composition may be formed using for example, free radical-induced polymerisation, by halogenating U and/or X, and using metal-mediated cross coupling or standard alkyne coupling chemistry (Advanced Organic Chemistry, J March, Wiley Interscience, 4th Edition, p449-463; p714-715; p194; and p744). Alternatively, or additionally, if X represents CHxe2x95x90CH2 or Cxe2x89xa1CH and the insoluble support is a polymeric compound having no complementary U groups, then the photosensitizable compound may be linked to the polymeric support by using a dopant, such as an acrylic acid. The dopant may be incorporated into the polymeric support to provide a binding site for the photosensitizable compound or the dopant may be bonded to the photosensitizable compound and the resultant compound copolymerized with the polymeric support.
Reagents such as carbodiimides, 1,1xe2x80x2-carbonyldiimidazole, cyanuric chloride, chlorotriazine, cyanogen bromide and glutaraldehyde, and processes such as use of mixed anhydrides, reductive amination and metal-assisted cross-couplings of halogenated compounds with organometallic compounds may also be used to couple the photosensitizable compound to the insoluble support.
In one particular embodiment, when the photosensitizable compound represents a benzoporphyrin, a purpurin, a chlorophyll, an haematoporphyrin, a phorbine, a bacteriochlorin or a porphyrinogen having a group X representing CHxe2x95x90CH2, the photosensitizable compound may be co-polymerised with monomers, such as plastics made from unsaturated monomers (ie polyethylene, polypropylene, polyacrylates, polystyrene, polyamide) by processes such as free radical induced polymerisation to give either rigid or flexible insoluble polymeric matrices incorporating the desired photosensitizable compound.
In a further embodiment, when the photosensitizable compound represents a benzoporphyrin, a porphycene, a purpurin, a chlorophyll, an haematoporphyrin, an etiopurpurin, a phorbine, a verdin, a bacteriochlorin or a porphyrinogen having a group X representing CO2R20, the photosensitizable compound may be incorporated into a polymer having a NHR15 group via amide bond formation by techniques which are well-known to those skilled in the art. Alternatively, the photosensitizable compound may be incorporated into a polymer having a carboxyl group by formation of a diamide type linkage using a bis-amino spacer.
In a further embodiment, when the photosensitizable compound represents a porphycene having a group X representing NHR15, then the photosensitizable compound may be incorporated into a polymer having a CO2R20 group via amide bond formation by techniques which are well-known to those skilled in the art. Alternatively, the photosensitizable compound may be incorporated into a polymer having an amino group by formation of a urea type linkage.
In yet a further embodiment, when the photosensitizable compound is an haematoporphyrin, a phorbine or a porphyrinogen having a group X representing OH, then the photosensitizable compound may be incorporated into a functionalised silica group, such as a glass, by formation of a silyloxy linkage by methods well known to those skilled in the art.
In a further embodiment, when the photosensitizable compound is a phorbine or a bacteriochlorin having a group X representing SH, then the photosensitizable compound may be bonded through the sulphur atom to the surface of a noble metal, such as metallic gold, thus forming a thio ether or disulfide linkage by methods well known to those skilled in the art.
In a further embodiment, when the photosensitizable compound is a chlorphyrin having a group X representing Cxe2x89xa1CH, then the photosensitizable compound may be copolymerised with monomers, such as plastics made from unsaturated monomers (ie polyethylene, polypropylene, polyacrylates, polystyrene, polyamide) or the photosensitizable compound may be incorporated into a polymer having a halo, Cxe2x89xa1CH, CHxe2x95x90CH2, MgCl or ZnCl group by processes such as free radical-induced polymerisation or metal mediated cross-coupling to form either rigid or flexible insoluble polymeric matrices incorporating the photosensitizable compound.
Where the photosensitizable compound is derived from natural sources, advantage may be taken, for instance, of vinyl or carboxyl groups that are present in the native compound. The isolation and/or synthesis of such photosensitizable compounds as previously defined for a compound of formula I are described for example in Bonnett R. xe2x80x98Photosensitizers of the Porphyrin and Phthalocyanine Series for Photodynamic Therapyxe2x80x99, Chemical Society Reviews (1995), 19-34; Dougherty T J xe2x80x98Is PDT a Useful Cancer Treatment?xe2x80x99, International Photodynamics (1995) 1(2), 2-3; Lin C-W xe2x80x98Photodynamic Therapy of Malignant Tumorsxe2x80x94Recent Developmentsxe2x80x99, Cancer Cells (1991) 3(11), 437-444; Garbo G M xe2x80x98Purpurins and benzochlorins as sensitizers for photodynamic therapyxe2x80x99, Journal of Photochemistry and Photobiology B: Biology (1996) 34, 109-116; Braslavsky S E et al. xe2x80x98Photophysical Properties of Porphycene derivatives (18 xcfx80 porphyrinoids)xe2x80x99, Journal of Photochemistry and Photobiology B: Biology (1997) 40, 191-198.
Alternatively, these and other functionalities may also be introduced into the photosensitizable compound using the appropriate chemistry on suitably protected precursor molecules. For example, carboxyl groups may be activated by conversion to the corresponding acid chloride, azide or activated ester and then incorporated into a construct by treatment with a polymeric matrix bearing nucleophilic substituents.
The following reaction scheme is one example of a route to the compositions of the present invention comprising a photosensitizable compound and the insoluble support, which is preferably a compound of formula XIV or XV, where the photosensitizable compounds are synthesised for incorporation into the insoluble support to form a construct: 
By appropriate protection strategies, linkage of the photosensitizable compound to support matrices can be made through specific functional groups in multi-functional molecules.
It is evident to those skilled in the art that the synthetic steps need not always be carried out in the specific order given above but that flexibility exists in the routes especially in the order of performing the steps of protection and deprotection, or whether protection is used at all, the metal insertion reaction, the purification steps, any reduction operations, and the functionalisation and attachment or incorporation steps.
The precursors may be synthesised using methods such as standard peptide chemistry described in the literature, for example in Houben Weyl, Methoden der Organischen Chemie, Parts 1 and 2, Vol 15. If necessary the carboxyl, amino, hydroxyl or thio functionalities of the precursor molecules may be protected using suitable reversible protecting groups. The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J W F McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
The protected precursor molecules may be condensed with spacer molecules such as natural amino acids or other linkers by methods well known to those skilled in the art to give mixtures of derivatised protected photosensitizable compounds (for subsequent covalent linkage to preformed polymeric supports) which are enriched in the desired photosensitizable compound by appropriate choice of the relative amounts of the precursors and the conditions of the condensation reaction.
The desired photosensitizable compound may be isolated by chromatographic separation or crystallisation. These procedures can be optimised by judicious choice of the groups R combined with reversible optional protection of the function in the side-chain, if appropriate. At this point it can be advantageous to insert the metal atom into the macrocycle. The functional group, where appropriate, is activated or derivatised, and the macrocycle can be attached to a surface or copolymerised with a suitable comonomer. At various points in the sequence of reactions, it is possible to manipulate the photosensitizable compound structure when separation of any isomers is desired.
The compositions of the invention are photodynamic as they emit reactive oxygen species, such as singlet oxygen or oxygen free radicals, following irradiation with light of the appropriate wavelength in the presence of oxygen. Consequently, the compositions of the invention are suitable for use in the curative and/or prophylactic treatment of a medical condition for which a photodynamic agent is indicated. Preferably, the compositions of the invention arc suitable for use in the curative and/or prophylactic treatment of atherosclerosis; cataracts; restenosis; secondary cataracts; endometrial ablation; cancers such as bladder cancer; other proliferative diseases; bacterial infections such as Gram-positive cocci (eg Streptococcus), Gram-negative cocci (eg Neisseria), Gram-positive bacilli (eg Corynebacterium species) Gram-negative bacilli (eg Escherichia coli) acid-fast bacilli (eg a typical Mycobacterium) and including infections causing abscesses, cysts, arthritis, urinary tract infections, pancreatitis, pelvic inflammatory disease, peritonitis, prostatitis, vaginal infections, ulcers and other localised infections; actinomyces infections; fungal. infections such as Candida albicans, Aspergillus and Blastomyces; viral infections such as HIV, encephalitis, gastro-enteritis, haemorrhagic fever, hantavirus, viral hepatitis, herpesvirus (eg cytomegalovirus, Epstein-Barr, herpesvirus simiae, herpes simplex and varicella-zoster); protozoal infections such as amoebiasis, babesiosis, coccidiosis, cryptosporidiosis, giardiasis, Leishmaniasis, Trichomoriasis, toxoplasmosis and malaria; helminthic infections such as caused by nematodes, cestodes and trematodes, eg ascariasis, hookworm, lymphatic filariasis, onchocerciasis, schistosomiasis and toxocariasis; and inflammatory diseases such as soft-tissue rheumatism, osteoarthlritis, rheumatoid arthritis and spondyloarthropathies. The cytotoxicity of the photodynamic therapy may kill the infecting cells (in the case of bacteria or fungi) or the affected host cells (in the case of viral infections and inflammatory disease).
In a particular preferred composition the insoluble support is a noble metal film, preferably the noble metal is gold and the thickness of the film is 10 to 1000 nm. When the support is gold, X in a compound of the invention of formula I or a photosensitizable compound of formula XVI may represent SH or Sxe2x80x94]2. The compound of formula I or the photosensitizable compound is bonded through the sulphur atom to the surface of the metallic gold thus forming a thio ether or disulphide linkage.
A noble metal film coated with a compound of the invention or a photosensitizable compound may be prepared by immersing the film in a solution of a compound of formula I, wherein X represents SH or Sxe2x80x94]2, in a suitable solvent, such as hexane, chloroform or dichloromethane, at room temperature for up to 24 hours, optionally with stirring.
In a further preferred composition the insoluble support includes a glass surface and X in the compound of formula I or X in the photosensitizable compound of formula XVI may represent Si(halo)3, particularly Si(Cl)3. The photosensitizable compound is then bonded through the silicon atom to the glass surface
The compositions of the invention may be fabricated into or coated on various medical devices and surgical implants, such as balloon catheters, vascular stents, intraocular lenses, orthopacdic implants, other artificial surgical implants, interfaces, artificial joints, surgical screws and pins. Each of the medical devices may also optionally include an integrated light delivery system.
A vascular stent is a permanent implant comprising a mesh-like tube which is used to maintain an open lumen within the blood vessels. Typically, a vascular stent is made from metal, stainless steel, nickel, platinum, all of which are optionally coated with a polymer to increase biocompatability. Alternatively, the stent may be made completely from polymers or plastics.
In a typical surgical procedure, the stent is delivered to the target site in a blood vessel with a guide catheter, usually after a patient has been administered a bolus of heparin. Preferably, the guide catheter has a retractable sheath which shields the stent until it is at the target site. After the catheter has been directed to the target site. After the catheter has been directed to the target site possibly with the aid of a contrast medium, the sheath is retracted to expose the stent. The stent either self expands or it is expanded with an inflatable balloon of a balloon catheter. The stent delivery system, balloon and catheter are removed leaving the stent within the blood vessel.
An intraocular lens is a lens that is adapted to be fixed to the periphery of the iris or an opening in the capsular bag of the eye. Typically, the lens is made from an acrylic polymer, such as polymethyl methacrylate or hydroxyethyl methacrylate, optionally coated with a biocompatible polymer such as phosphorylcholine. A suitable intraocular lens (IOL) is described in U.S. Pat. No. 5,716,364, which is incorporated herein by reference. The IOL is made of a polymeric material such as a polyolefin, for example polypropylene.
Preferably, the coating is a molecular monolayer that partially or totally coats the surface of the medical device.
The coating may be fixed to the medical device by forming a bond between the xe2x80x94ZX functional group of the compound of the invention of formula I or a photosensitizable compound of formula XVI and the reactive U functional groups of the insoluble support as previously defined. For example, the coating may be fixed to a balloon catheter with covalent bonds, such as ether, ester, ainide, amine, carbamate, urea, keto, poly(alkyloxy), xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Si(OR17)2xe2x80x94, xe2x80x94SiR18R19xe2x80x94, xe2x80x94SiR17R18xe2x80x94, amino alcohol, amino acyl, lower alkenyl, aryl or lower alkylaryl linkages, using methods which are well known to those skilled in the art.
Alternatively, the coating may be formed by reacting the compounds or compositions of the invention with the polymeric precursors of a medical device prior to formation of the medical device.
It will be appreciated that when the medical device comprises a silica based polymer optionally having reactive or functionalised silica groups, such as a silicone polymer, the medical device also acts as the insoluble support and it may be coated and/or impregnated by direct reaction with a compound of the invention of formula I or a photosensitizable compound of formula XVI. The compound of the invention or the photosensitizable compound is bonded to the silicone polymer with one of the linkages as previously disclosed herein.
The medical devices enable the compounds of the invention and the photosensitizable compounds to be delivered to a particular target tissue. For example, in the treatment of atherosclerosis/restenosis the target cells arc the smooth muscle cells on the blood vessel lumen surface, and inflammatory cells such as macrophages, whereas in the treatment of cataracts the target cells are the lens epithelial cells on the inner surface of the capsular bag which are typically aggregated around the periphery of the capsular bag. This site specific delivery reduces or substantially eliminates undesirable side-effects associated with photodynamic agents residing in and accumulating in non-target tissues. This increases patient compliance as a patient who has been treated with a medical device of the present invention only needs to shield the treated tissue from exposure to light, rather than other parts of the body which may be necessary with photodynamic agents having no site specific delivery system.
Typically, following absorption of light of the approximate wavelength, preferably 500 to 800 nm, the coating of the medical device emits reactive oxygen species, such as singlet oxygen, which travel a distance of between 50 nm and 5 nm (micrometers) from the device depending on the composition of the medium surrounding the device. For example, if the medium is a biological tissue then the reactive oxygen species travel between 10 and 50 nm from the device, whereas the reactive oxygen species travel approximately 1 to 5 xcexcm from the device when the medium is a saline solution, even greater distances 10 to 100 xcexcm can be achieved in other liquids, alcohols, acetone and aqueous mixtures thereof.
Each of the medical devices may also include a fluid delivery system for delivering desired medium to the coating of the device. Hence, and in contrast to the small limited distances (eg 10-50 nm) of emission of reactive oxygen species from photodynamic sensitisers administered directly into cells, the distance the reactive oxygen species emitted from the devices of the present invention may be controlled accurately. This further reduces the undesirable side-effects associated with reactive oxygen species interacting with non-target tissue and thereby further increases patient compliance.
It will be appreciated that the material introduced into the body will be sterile and may also be non-pyrogenic. Sterility is typically achieved by conventional temperature, pressure, radiation or chemical sterilisation treatment techniques, preferably during the manufacture of the devices.
In a further aspect, the present invention provides methods for treating or preventing cataracts, secondary cataracts, bladder cancers, restenosis, atherosclerosis, endometrial ablation, other cancers and proliferative diseases, inflammation and infection using the medical devices of the invention.
In yet a further aspect, the present invention provides a method of producing light-induced singlet oxygen which comprises irradiating a compound or composition of the invention with light of the appropriate wavelength preferably 500 to 800 nm, in the presence of oxygen.